Cardiovascular disease and its associated maladies, dysfunctions and complications are a principal cause of disability and the chief cause of death. One specific factor significantly contributing to this pathophysiologic process is atherosclerosis, which has been generally recognized as the leading health care problem both with respect to mortality and health care costs.
Atherosclerosis is characterized by the deposition of fatty substances, primarily cholesterol, resulting in plaque formation on the inner surface of the arterial wall and degenerative change to the arteries.
It is now well established that cardiovascular disorders including myocardial infarction, coronary heart disease, hypertension and hypotension, cerebrovascular disorders including stroke, cerebral thrombosis and memory loss due to stroke; peripheral vascular disease and intestinal infarction are caused by blockage of arteries and arterioles by atherosclerotic plaque. Atherosclerotic plaque formation is multi-factorial in its production. Hypercholesterolemia, especially elevated levels of low-density lipoprotein cholesterol (LDL), is an important risk factor for atherosclerosis and arteriosclerosis and associated diseases.
The HMG-CoA reductase inhibitors (statins) have been used in reducing blood levels of LDL cholesterol. Cholesterol is produced via the mevalonic acid pathway. Reducing the formation of mevalonic acid, a precursor to cholesterol, leads to a corresponding decrease in hepatic cholesterol biosynthesis with a reduction in the cellular pool of cholesterol.
U.S. Pat. No. 4,681,893 assigned to Warner-Lambert, discloses certain trans-6-[2-(3-, or 4-carboxamido-substituted pyrrole-1-yl)alkyl]-4-hydroxypyran-2-ones and the corresponding ring-opened hydroxy acids derived therefrom, including trans(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydrohydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, which are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA), an important coenzyme catalyzing the intracellular synthesis of cholesterol.
U.S. Pat. No. 5,273,995 assigned to Warner Lambert, relates to the optically pure (R,R) form of the ring-opened acid of trans-5-(4-fluorophenyl)-2-(1-methylethyl-N,4-diphenyl-1-[2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide that is [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, pharmaceutically acceptable salts thereof, specifically its calcium salt (Atorvastatin, Lipitor®), which is currently being used for the treatment of hypercholesterolemia.
U.S. Pat. No. 5,385,929 discloses certain phenyl hydroxy derivatives of the compounds disclosed in U.S. Pat. No. 5,273,995, and that such phenyl hydroxy derivatives are also active as the inhibitors of the biosynthesis of cholesterol.